Abstract A9: Uridine diphospho glucuronosyl-transferase 2B17 genotype and a risk of acute lymphoblastic leukemia and lymphoblastic lymphoma among Japanese children

Abstract

Abstract Background: Using clinical samples and tumor cell lines, chromosomal aberrations and somatic mutations have been well explored in the field of pediatric oncology. However, genes susceptible to pediatric acute lymphoblastic leukemia (ALL) as well as lymphoblastic lymphoma (LBL) have not been delineated yet. Therefore, we examined copy number variations (CNVs) of genomic DNA by means of high-resolution comparative genomic hybridization (CGH) microarray to find significant susceptible genes to ALL and LBL. Methods: We investigated CNVs by array CGH in genomic DNA derived from a total of 58 children with ALL and LBL as case, and compared with control I (n=67): acute myeloid leukemia (AML)(n=10), other type of leukemia (n=4), non-LBL (n=7) and solid tumors such as neuroblastoma (n=46) as well as control II (N=301): adults patients with diabetic nephropathy and receiving dialysis (n=86), with neurological diseases (n=76) and with esophageal, gastric and colon cancers (n=72) plus control I (n=67). Normalization was performed using the Log2 signal ratio (sample DNA/control DNA) for individual 180K probes distributed throughout the whole genome. Control DNA was obtained from a single Japanese person. To compare data between two groups (e.g., ALL+LBL vs. control I or control II), an unpaired t test was used and subsequently corrected by the Benjamini-Hochberg false-discovery rate using GeneSpringGX v.11.5.1. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.8 or less than -1.8 were considered statistically significant. Significant gene was confirmed using real time polymerase chain reaction (PCR). Results: CNV of uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) gene was statistically less deleted in children with ALL+LBL, compared with control I (q-value=5.51 x 10-12) and with control II (q-value=6.58 x 10-6). Presence or absence of UGT2B17 gene was reconfirmed by real time PCR. CNVs of other genes were similar in cases and controls. UGT2B17 glucuronidates several endogenous and exogenous compounds in particular steroid hormones as well as several pharmaceutical drugs such as anthraquinones and histone deacetylase inhibitor. As previously reported in some paper of adult solid tumors, CNV of UGT2B17 gene showed significant correlation to drug response. The frequency of CNV shows exceptional differences between populations from Africa, Europe, and Asia. Interindividual variability in UGT2B17 allele-frequency is accompanied by pronounced differences in gene expression characterized by more than 29 times higher mRNA levels in Caucasian compared with Japanese. Conclusion: These results suggest that homozygous or heterozygous gains of the UGT2B17 gene may be associated with a significant risk for pediatric ALL and LBL. Citation Format: Sae Ishimaru, Yuya Saito, Yuichi Yokokawa, Yuki Yuza, Takashi Kaneko, Mitsuyoshi Urashima. Uridine diphospho glucuronosyl-transferase 2B17 genotype and a risk of acute lymphoblastic leukemia and lymphoblastic lymphoma among Japanese children. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A9.